Complex small molecules made by bacteria are the centerpiece in the struggle against infectious disease. As antibiotic resistance among pathogens continues to spread, the need to discover novel biologically active molecules, also called natural products, grows more exigent. New evidence has led to the hypothesis that in the soil environment, many natural products may act as signaling molecules between bacterial strains or species. As most natural product discovery efforts have not accounted for this hypothetical function in their design, the overwhelming majority of these molecules have gone undetected. The research outlined in this proposal seeks to remedy this problem by incorporating the communicative nature of these molecules as a driver to stimulate production of novel natural products from several species of soil-dwelling, actinomycete bacteria. Specifically, we propose in three aims to (1) To mine the genomes of five newly sequenced streptomycete strains for natural product genes and generate a reporter strain library;(2) To identify conditions which induce natural product gene expression in multiple high-throughput screens (including A: in response to cultivation in proximity to other microbial strains/species and B: in response to stimulation by a library of thousands natural products.);and (3) Characterize and screen newly discovered natural products for antimicrobial and antitumor activity. The research proposed here is designed to simultaneously yield novel natural products of therapeutic value and investigate the hypothesis that these secondary metabolites act as signalling molecules in their natural context. Understanding the functions of these biologically active molecules in the natural environment will suggest ways to improve the efficiency of future discovery efforts and better ways to utilize natural products in the clinical arena. PUBLIC HEALTH RELEVANCE: The discovery of antibiotics made by bacteria revolutionized modern medicine. However, resistance among pathogens is on the rise, prompting a need to find new, more effective antibiotic molecules. New evidence has led to the hypothesis that in the natural environment, these molecules (called natural products) actually serve as signals between interacting microbes. The research outlined here will both test this hypothesis and utilize these interactions to stimulate the production of potentially useful novel natural products by several species of soil-dwelling bacteria. In addition to finding novel natural products, this work will allow us to bring more focus to our screening designs, thus enhancing the speed and efficiency of our future natural product discovery efforts